Entecavir (structural formula 1, shown below) is an anti-viral compound used in the treatment of hepatitis B infections in humans. It is marketed under the trade name “Baraclude”, as oral tablets and solutions.

Prior art methods of making entecavir involve protection of hydroxyl and hydroxymethyl groups on a cyclopentane starting material with silyl protecting groups; while chemical reaction and derivatization of other groups to form the entecavir molecule are conducted. The silyl protecting groups are removed by hydrolysis in a final or close to final synthetic process step.
Canadian Patent Application No. 2,705,953, incorporated herein by reference, discloses a process for preparation of entecavir and similar carbonucleoside compounds, which avoids the use of such silyl protecting groups.
In the preparation of carbonucleosides, coupling using guanine can be challenging and can lead to carbonucleosides having different stereochemistry. Moreover, use of guanine in forming carbonucleosides can lead to undesired side-products, such as, coupling of the guanine at the N2, N7 or O6 position rather than at the N9 position. These side products can be difficult to isolate and purify from the N9 product. This is addressed to some extent by using a guanine derivative that has a halide, such as chlorine or iodine, at the O6-position, to obtain an intermediate carbonucleoside. This intermediate carbonucleoside is further reacted to obtain the guanine based carbonucleoside. However, such a procedure does not avoid coupling at the N2 or N7 position. Furthermore, additional processing steps are required to obtain the desired product.
Therefore, there is a need in the art for a process for preparation of guanine based carbonucleoside that can lead to higher selectivity in coupling guanine at the N9 position and can also be stereoselective. In addition, there is a need in the art for a process that avoids use of protecting groups requiring different conditions for deprotection. Hence, there is a need in the art for a process where a final global deprotection can be performed in a single step.